The SLAM family of receptors is emerging as key players in the fine tuning of immune responses and facilitating lymphocyte:lymphocyte interactions. They are able to function as either inhibitory or stimulatory receptors depending upon their association with key signaling adaptors that bind to tyrosine based motifs in their cytoplasmic tails. The SLAM family receptor, CD244 is expressed on all NK cells and is able to regulate NK cell mediated cytotoxicity and cytokine secretion. In the human, its stimulatory function is completely dependent on the association with the adaptor, SAP. The loss of SAP function also contributes to the fatal syndrome, XLP. We have recently found that in the mouse, two major haplotypes (b and z) of the SLAM family gene cluster exist and haplotype divergence has been associated with a murine model of lupus. We have studied CD244 function in the context of these haplotypes and found that polymorphisms at the CD244 locus result in divergent function of CD244 with the z haplotype exhibiting activating and the b haplotype inhibitory signaling. Defining how these polymorphisms lead to divergent CD244 function and the consequence of that on NK cell biology and the interface between the innate and adaptive immune responses are our long-term goals. We propose to address this in the following specific aims: 1. To elucidate the molecular mechanisms responsible for divergent CD244 function. 2. To generate transgenic mouse strains which differ solely in their expression of CD244 alleles. 3. To examine the affect of divergent CD244 function on NK cell responses to tumors.